Infection with hepatitis B virus is a major cause of liver disease worldwide and accounts for 5-10 per cent of chronic liver disease and cirrhosis in the United States. Safe and effective vaccines are available for prevention of hepatitis B, but therapies for the disease once it has occurred are limited in efficacy. Alpha interferon was the first antiviral agent shown to be effective in this disease and was licensed for this indication in 1993. A modified, long-acting form of interferon -peginterferon- was licensed for use in hepatitis B in 2005. The basis for licensure were, in part, studies conducted by the Liver Diseases Section, NIH. However, alpha interferon is effective in one-third or less of patients with typical chronic hepatitis B and its role in atypical forms remains unclear. More recently, several nucleoside and nucleotide agents have been shown to be effective in treating chronic hepatitis B and have now been licensed for use in the United States. These include lamivudine, adefovir and entecavir. These agents are safe and cause suppression of HBV DNA to low levels and improvements in biochemical and histologic evidence of disease. However, withdrawal of nucleos(t)ide therapy is almost always followed by relapse and return of disease activity. Furthermore, long-term therapy can lead to antiviral resistance and loss of potency. Current activities in the Liver Diseases Section are focused on developing better therapies to prevent long-term consequences and analysis of immunological factors that predict or correlate with outcome of treatment. A longterm study of lamivudine (3-thiacytidine) for both HBeAg positive and anti-HBe positive chronic hepatitis B has been underway since 1996 and was recently modified to allow for continued therapy. A total of 49 patients were enrolled into this study. Virtually all patients had a serum biochemical, virological and histological response to lamivudine in a dose of 100 mg once daily. However, breakthrough with viral resistance has occurred in 80% of patients who were initially HBeAg positive and 50% of those initially anti-HBe positive (and HBeAg negative). Liver biopsies taken after 3 to 5 years of therapy show marked improvements in patients who maintained a viral response, but little or no long-term improvement in those with viral resistance. Most striking has been a resolution of fibrosis in patients with a long-term maintained response to therapy and, in some cases, return of the liver biopsy to normal despite persistence of HBsAg in serum. These patients appear to be tolerant of hepatitis B and lack T cell responsiveness to HBV antigens. A current protocol will focus upon transient withdrawal of lamivudine therapy in patients with a long-term response with frequent monitoring of viral levels, serum aminotransferases, and immunological responses to HBV antigens. Transient withdrawal of viral suppression may lead to triggering of immune reactivity to HBV and clearance of virus and HBsAg. Another central issue is how to manage patients who develop lamivudine resistance. Patients with resistance demonstrating progression of disease have been treated with alpha interferon which has induced transient improvements but without clearance of HBeAg. Two protocols have been developed to use the oral nucleotide analogue, adefovir for chronic hepatitis B: one for patients with lamivudine resistance (developed in collaboration with the Laboratory of Immune Regulation, NIAID) and one for previously untreated patients who will be randomized to receive either the combination of lamivudine and adefovir or adefovir alone longterm with similar monitoring and follow up as done for patients who received lamivudine monotherapy. A total of 32 patients have been enrolled into this study. Results to date indicate similar rates of response to adefovir alone as to adefovir and lamivudine in combination, but the combination provides more potent inhibition of HBV DNA levels (5.94 vs 3.88 log decrease) and a virologic response in all patients, compared to only two-thirds of patients treated with adefovir alone. The relative efficacy of long-term therapy will continue to be evaluated, and a total of 40 patients will be needed to adequately power this analysis of combination versus monotherapy with adefovir. These studies will help define the efficacy and safety of long-term, continuous antiviral therapy of hepatitis B.